Prevalence and clinical profile of celiac disease in type 1 diabetes mellitus in north India

Background and Aim: There is scanty data on the occurrence of celiac disease in patients with type 1 diabetes mellitus in South Asia. Our aim was to study the prevalence and clinical profile of celiac disease in patients with type 1 diabetes mellitus in a tertiary care referral centre in north India. Methods: Consecutive patients of type 1 diabetes mellitus attending the Endocrine clinic of our institute between January 2002 and December 2008 were screened using anti‐tissue transglutaminase antibodies (tTGAb), and those positive were subjected to duodenal biopsy. Clinical profile of these patients was recorded. Results: Out of 189 patients of type 1 diabetes mellitus, 21 (11.1%) were diagnosed to have celiac disease on the basis of positive serology (tTGAb) and duodenal histology. The mean age at diagnosis of diabetes was 10.81 ± 7.3 years and that of celiac disease was 13.74 ± 5.71 years, with a difference of 5.18 ± 4.75 years between the two. Only 2/21 patients with celiac disease had been diagnosed before detection of diabetes mellitus. Short stature was the commonest (52.3%) manifestation of celiac disease, followed by anemia (47.3), weight loss (42.8%), diarrhea (28.6%) and abdominal pain (14.2%). After initiating gluten free diet, 14/16 symptomatic patients had reversal of anemia, weight loss and diarrhea. Growth rate velocity improved from 2.3 ± 1.0 cm/year to 5.5 ± 2.4 cm/year in those with short stature. Conclusion: Celiac disease is highly prevalent in patients with type 1 diabetes mellitus (11.1%) and majority of them (90.5%) were diagnosed on screening. Routine screening is required for early diagnosis and combat associated co‐morbidities.     

Genetics and pathogenesis of type 1 diabetes: prospects for prevention and intervention

Type 1 diabetes is etiologically a multifactorial disease caused by a complex interaction of genetic and environmental factors, with the former consisting of multiple susceptibility genes. Identification of genes conferring susceptibility to type 1 diabetes would clarify etiological pathways in the development and progression of type 1 diabetes, leading to the establishment of effective methods for prevention and intervention of the disease. Among multiple susceptibility genes, HLA and INS are particularly important because of their contribution to tissue specificity in the autoimmune process. DRB1*04:05‐DQB1*04:01 is associated with autoimmune type 1 diabetes, idiopathic fulminant type 1 diabetes and anti‐islet autoimmunity in autoimmune thyroid diseases, suggesting that this haplotype is associated with beta‐cell specificity in autoimmune diseases. Genes involved in the expression of insulin in the thymus contribute to beta‐cell‐specific autoimmune mechanisms in type 1 diabetes. These genes and pathways are important targets for tissue‐specific prevention and intervention of type 1 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00176.x, 2011)     

Celiac disease in a rheumatology unit: a case study

The objective of the study is to present a series of 20 patients who have been attending a rheumatology unit and were diagnosed with celiac disease in adult life. The record-charts of 20 Italian not consanguineous patients affected by celiac disease (1 man and 19 women, mean age of 46.7), diagnosed at >16 years of age, followed by a rheumatology unit were reviewed (group 1). Any other autoimmune disease diagnosed in the patients were given was recorded; moreover, the reason for rheumatologist evaluation was registered as well as the presence of symptoms suggestive of celiac disease and the obstetric history. The clinical features were compared with those of a group of 40 celiac patients (8 men and 32 women, mean age of 43.1) followed by a medicine department (group 2); even in these cases the diagnosis of celiac disease was performed in adult life. Sixteen out of 20 patients in Group 1 were diagnosed as suffering from celiac disease by the rheumatologist. Seventeen concomitant autoimmune disorders among which nine were connective tissue diseases were found in 15 patients. The main reason for rheumatologist evaluation was arthromyalgias. Ten patients showed one or more clinical features suggestive of celiac disease; moreover, eight patients had a history of sideropenic anemia. After the adoption of a gluten-free diet there were three pregnancies that all ended with alive newborns, differently from the obstetric history before celiac disease diagnosis, characterized by a relevant number of miscarriages and foetus deaths. In Group 2, a total of ten autoimmune diseases concomitant with celiac disease were found in eight patients; autoimmune thyroid disorders represented the most frequent cases. No connective tissue diseases were recognized. Celiac disease may coexist with connective tissue diseases; the recognition of this association is difficult because celiac disease may present with atypical or even symptomless forms or in some cases may resemble a multisystem disorder or may mimic a rheumatologic condition; on the other hand, the variety of symptoms of rheumatic disorders may make difficult the diagnosis of celiac disease in association with a systemic autoimmune disease. These confounding factors often lead to a delay in performing the right diagnostic formulation.     

Capsule endoscopy in celiac disease

Video capsule endoscopy is an attractive and patient- friendly tool that provides high quality images of the small bowel. Obscure gastrointestinal bleeding is the primary and most evaluated indication to capsule endoscopy; however, indications are expanding and a small number of preliminary reports have been presented concerning the role of video capsule endoscopy in the diagnosis of celiac disease. The purpose of this review is to update the current knowledge and to hypothesize on future perspectives of the use of video capsule endoscopy in patients with celiac disease.     

Antibodies from a patient with type 1 diabetes and celiac disease bind to macrophages that express the scavenger receptor CD163

Antibodies against the wheat storage globulin Glo-3A from a patient with both type 1 diabetes (T1D) and celiac disease were enriched to identify potential molecular mimicry between wheat antigens and T1D target tissues. Recombinant Glo-3A was used to enrich anti-Glo-3A immunoglobulin G antibodies from plasma by batch affinity chromatography. Rat jejunum and pancreas, as well as human duodenum and monocytes were probed, and binding was evaluated by immunohistochemistry and confocal microscopy. Glo-3A-enriched antibodies bound to a specific subset of cells in the lamina propria of rat jejunum that co-localized mostly with a marker of resident, alternatively activated CD163-positive (CD163⁺) macrophages. Blood monocytes and macrophage-like cells in human duodenum were also labelled with the enriched antibodies. Blocking studies revealed that binding to CD163⁺ macrophages was not due to cross-reactivity with anti-Glo-3A antibodies, but rather to non-Glo-3A antibodies co-purified during antibody enrichment. The novel finding of putative autoantibodies against tolerogenic intestinal CD163⁺ macrophages suggests that regulatory macrophages were targeted in this patient with celiac disease and T1D.     

Zonulin as a potential putative biomarker of risk for shared type 1 diabetes and celiac disease autoimmunity

The incidence of type 1 diabetes (T1D) is increasing annually, in addition to other childhood‐onset autoimmune diseases. This review is inspired by recent strides in research defining the pathophysiology of autoimmunity in celiac disease, a disease that has significant genetic overlap with T1D. Population genetic studies have demonstrated an increased proportion of newly diagnosed young children with T1D also have a higher genetic risk of celiac disease, suggesting that shared environmental risk factors are driving the incidence of both diseases. The small intestine barrier forms a tightly regulated interface of the immune system with the outside world and largely controls the mucosal immune response to non‐self‐antigens, dictating the balance between tolerance and immune response. Zonulin is the only known physiological modulator of the intercellular tight junctions, important in antigen trafficking, and therefore, is a key player in regulation of the mucosal immune response. While usually tightly controlled, when the zonulin pathway is dysregulated by changes in microbiome composition and function, antigen trafficking control is lost, leading to loss of mucosal tolerance in genetically susceptible individuals. The tenant of this hypothesis is that loss of tolerance would not occur if the zonulin‐dependent intestinal barrier function is restored, thereby preventing the influence of environmental triggers in individuals genetically susceptible to autoimmunity. This review outlines the current research and a structured hypothesis on how a dysregulated small intestinal epithelial barrier, a “leaky gut,” may be important in the pathogenesis of autoimmunity in certain individuals at risk of both T1D and celiac disease.     

Prevalence of celiac disease in children with type 1 diabetes: A review

Background and aimsDiabetes mellitus is a chronic disease and a major health threat. Comorbidity of celiac disease and diabetes is associated with many complications in children, and if not diagnosed in time in diabetes children, caused complications, including gastrointestinal disorders, most importantly, growth disorders. Thus, this study aims to summarize the evidence about prevalence of celiac disease in children with type 1 diabetes through a systematic review approach.MethodsA literature review was conducted within databases. Observational studies that assessed the prevalence of celiac disease in diabetes children, were included. We assess the quality of included studies with STROBE checklist. Data extraction and assessment has guided by PRISMA checklist. Also, the data has reported by Garrard’s table.Results31 studies included that assessed 63,349 children with type 1 diabetes. Anemia, osteoporosis, and neurological disorders reported. Studies showed two main type of tests for diagnosis of CD included serological and intestinal biopsy. The prevalence of CD based serologic tests was higher than of intestine biopsy (1.4%–24.5% VS 1.1%–16.6%). In addition, the prevalence of celiac disease was different between populations.ConclusionsCeliac disease is an important comorbidity in children with type 1 diabetes, especially because of the similarity between CD symptoms and neuropathic and gastrointestinal symptoms of diabetes. Screening the diabetes children for celiac disease by serological tests and then intestinal biopsy is recommended.     

Contribution of HLA-DQ2/DQ8 haplotypes in type one diabetes patients with/without celiac disease

Background

Based on lack of data on the distribution of the related alleles in the T1D population in Iranian population, we assessed the frequency of HLA DQ2 and DQ8 haplotypes in patients with T1D with/without CD compared to healthy population.

Adult celiac disease in the elderly

There is an increased awareness that celiac disease may occur in the elderly although presentations with either diarrhea, weight loss or both may be less common causing delays in diagnosis for prolonged periods. Higher detection rates also seem evident owing to active case screening, largely through serodiagnostic measures. In some elderly patients who are genetically predisposed, it has been hypothesized that celiac disease might be precipitated late in life by an antigen, possibly from an infectious agent. As a result, peptide mimicry or other poorly-defined mechanisms may precipitate an autoimmune gluten-dependent clinical state. Although diarrhea and weight loss occur, only isolated iron deficiency anemia may be present at the time of initial diagnosis. In addition, the risk of other autoimmune disorders, particularly autoimmune thyroiditis, and bone disease, are increased. Osteopenia may also be associated with an increased risk of fractures. Finally, elderly celiacs have an increased risk of malignant intestinal disease, especially lymphoma.     

Prevalence and clinical features of celiac disease in 950 children with type 1 diabetes in France

The prevalence of celiac disease is higher in children with type 1 diabetes mellitus (DM) than in the general pediatric population, but may vary widely across countries. Sensitive and specific antibody tests are available for detecting celiac disease.

Aims

To evaluate the prevalence in France of histologically documented celiac disease in a vast cohort of children with type 1 DM, and to describe the features of celiac disease and treatment response.

Methods

Retrospective cohort study of 950 children with type 1 diabetes seen between 1994 and 2001. Antibodies to gliadin, reticulin, endomysium and transglutaminase were looked for one to seven times in each patient.

Results

Fifteen patients (1.6%) had biopsy-confirmed celiac disease. Symptoms led to the diagnosis in six patients (mean age, 7 years) and screening tests in nine patients (mean age, 11 years). Anti-endomysium antibodies were consistently positive. Tests for HLA-DQB1 0201 and/or 0302 were positive. Anti-endomysium antibody seroconversion was seen in two patients, 2 and 6 years, respectively, after the diagnosis of diabetes. In another patient, the biopsy became abnormal 6 years after the first positive anti-endomysium antibody test (latent form). After a mean of 3 years on a gluten-free diet, significant increases were noted in body weight (P = 0.04) and insulin dose (P = 0.05); clinical symptoms completely resolved in five of the six symptomatic patients.

Conclusions

The prevalence of celiac disease is higher in children with type 1 DM than in the general pediatric population. Serological screening is useful for diagnosing asymptomatic celiac disease, detecting seroconversion and monitoring latent forms of disease.     

Refractory celiac disease

Refractory celiac disease (RCD) affects patients who have failed to heal after 6–12 months of a strict gluten-free diet (GFD) and when other causes of symptoms (including malignancy) have been ruled out. It may also occur in patients who previously had responded to a long-term GFD. RCD may be categorized as RCD1 (normal immunophenotype) and RCD2 (aberrant immunophenotype). RCD1 usually responds to a continued GFD, nutritional support, and therapeutic agents such as corticosteroids. In contrast, clinical response in RCD2 is incomplete and prognosis is often poor. RCD (particularly RCD2) is associated with serious complications, such as ulcerative jejunitis and enteropathy-associated T-cell lymphoma (EATL). Strict clinical and laboratory criteria should be used to diagnose RCD and specialized tests for aberrancy and clonality should be interpreted in the context of their sensitivity and specificity. Adequate nutritional support and anti-inflammatory treatment may even allow patients with RCD2 to attain a clinical remission.     

调节性B细胞与1型糖尿病

1型糖尿病主要是由T细胞介导的针对胰岛β细胞的自身免疫性疾病,然而B细胞在1型糖尿病发生、发展中也发挥重要作用,B细胞去除可用于治疗1型糖尿病.调节性B细胞是近来研究发现的一群具有免疫负向调控作用的B细胞亚群.在1型糖尿病中存在调节性B细胞数量和功能的异常.探索调节性B细胞在1型糖尿病发病机制中所起的作用将提供更多的理论依据,为1型糖尿病免疫治疗提供新靶点和新思路.     

胸腺与1型糖尿病发生机制关系的研究进展

胸腺是重要的免疫器官,在中枢免疫耐受方面发挥重要作用。1型糖尿病是慢性自身免疫性疾病,其发病机制是胰岛β细胞受T细胞介导的自身免疫性破坏,不能合成和分泌胰岛素。现有研究表明,胸腺内低水平表达各种器官特异性外周抗原,是其中枢免疫耐受的基础。研究显示人类和鼠胰岛素基因都可在胸腺内表达,胸腺内胰岛素表达水平低的个体可能缺乏胰岛素中枢免疫耐受,而成为糖尿病易感个体。另外调节胸腺器官特异性抗原表达的自体免疫调节子（AIRE）基因,可上调抗原的表达,该基因功能缺陷也会导致胸腺胰岛素中枢免疫耐受缺失。在胸腺表达的作用于T细胞的酶、蛋白或某些病毒可直接导致胸腺细胞功能障碍。上述因素共同作用的结果是导致中枢自身免疫耐受缺乏,胰岛β细胞遭受破坏并最终导致1型糖尿病的发生。     

天然免疫细胞在1型糖尿病中的作用

1型糖尿病（T1DM）是一种复杂的自身免疫性疾病,主要是由T、B细胞破坏胰岛β细胞所致.虽然病因不明,但最终一系列天然免疫细胞及特异性免疫细胞相互作用,导致胰岛β细胞损伤和T1DM的发生.对动物模型和T1DM患者的研究发现,单核/巨噬细胞、自然杀伤细胞、自然杀伤T细胞、树突状细胞和淋巴细胞相互作用可影响T1DM的发生、发展.因此,研究天然免疫细胞在T1DM发生、发展中的作用,可能为防治T1DM提供新的方向.     

Clinical and immunological features of celiac disease in patients with Type 1 diabetes mellitus

Celiac disease (CD) is one of the most frequent autoimmune disorders occurring in Type 1 diabetes mellitus (T1DM). The prevalence of CD in T1DM varies from 3 to 16%, with a mean prevalence of 8%. The clinical presentation of CD in T1DM is classified as symptomless in approximately half of cases, but a more accurate analysis often discloses a wide array of symptoms suggestive of CD. Both T1DM and CD show the same genetic background and an abnormal small intestinal immune response with inflammation and a variable grade of enteropathy. Serological screening for CD should be performed in all T1DM patients by means of antibodies to tissue transglutaminase at T1DM onset. T1DM patients found to be celiacs must be treated by a gluten-free diet. Potential CD cases (especially when asymptomatic) should be kept on a gluten-containing diet with a careful clinical and antibody follow-up, since many of them will not develop villous atrophy.     

Reproductive changes associated with celiac disease

Celiac disease is a mucosal disorder of the small intestine that may be triggered by dietary exposure to gluten in genetically-susceptible individuals.The disorder is often associated with diarrhea,malabsorption and weight loss along with other extra-intestinal complications.Reproductive changes have been described,including impaired fertility and adverse pregnancy outcomes possibly related to immune-mediated mechanisms or nutrient deficiency.Other possible pathogenetic factors that may alter placental function include maternal celiac disease autoantibodies binding to placental transglutaminase,and genetic mutations that may facilitate microthrombus formation.Reports noting activation during pregnancy or the puerperium may be important,and suggest that celiac disease may also be hypothetically precipitated by maternal exposure to one or more fetal antigens.     

Association between type 1 diabetes mellitus and remitting seronegative symmetrical synovitis with pitting edema: a case report

A 59-year-old female with type 1 diabetes and RS3PE had HLA types known to be associated with both diseases. Type 1 diabetes patients suffering from polyarthritis and pitting edema should be examined for possible RS3PE and glucocorticoid therapy may be indicated despite the diabetes.     

Potential reno-protective effects of a gluten-free diet in type 1 diabetes

Aims/hypothesis  Coeliac disease is common in type 1 diabetes. It is managed with a gluten-free diet, characterised by foods low in AGEs. We hypothesised that this diet would lead to lower plasma AGEs and be associated with reduced albuminuria. Methods  From a single paediatric clinic, we recruited 21 children with type 1 diabetes and biopsy-proven coeliac disease, and 38 individuals with diabetes alone. The groups were matched for age, sex, duration of disease and metabolic control. Participants completed a detailed clinical and dietary history. Blood samples were taken for HbA_1c, coeliac serology, thyroid function, serum IgA levels and plasma AGEs, and urine samples were obtained for estimation of the albumin/creatinine ratio (ACR). Results  All the individuals with coeliac disease were asymptomatic, with negative transglutaminase antibodies. There were no significant differences between the groups in terms of age (14 years), sex (29% male), duration of diabetes (7 years), mean HbA_1c (8.3%), lipid levels or treatment regimens. However, children with diabetes and coeliac disease had twofold lower levels of urinary ACR than with those diabetes alone (p = 0.04). This was associated with lower levels of circulating AGEs (p = 0.03). These associations were independent of metabolic control, diabetes management and other potentially confounding variables, such as household exposure to cigarette smoke. Conclusions/interpretation  Adherence to a gluten-free diet may provide additional benefits for individuals with coeliac disease, and potentially those with type 1 diabetes.     

Non-responsive celiac disease in children on a gluten free diet

BACKGROUNDNon-responsive celiac disease (NRCD) is defined as the persistence of symptoms in individuals with celiac disease (CeD) despite being on a gluten-free diet (GFD). There is scant literature about NRCD in the pediatric population.AIMTo determine the incidence, clinical characteristics and underlying causes of NRCD in children.METHODSRetrospective cohort study performed at Boston Children’s Hospital (BCH). Children < 18 years diagnosed with CeD by positive serology and duodenal biopsies compatible with Marsh III histology between 2008 and 2012 were identified in the BCH’s Celiac Disease Program database. Medical records were longitudinally reviewed from the time of diagnosis through September 2015. NRCD was defined as persistent symptoms at 6 mo after the initiation of a GFD and causes of NRCD as well as symptom evolution were detailed. The children without symptoms at 6 mo (responders) were compared with the NRCD group. Additionally, presenting signs and symptoms at the time of diagnosis of CeD among the responders and NRCD patients were collected and compared to identify any potential predictors for NRCD at 6 mo of GFD therapy.RESULTSSix hundred and sixteen children were included. Ninety-one (15%) met criteria for NRCD. Most were female (77%). Abdominal pain [odds ratio (OR) 1.8 95% confidence interval (CI) 1.1-2.9], constipation (OR 3.1 95%CI 1.9-4.9) and absence of abdominal distension (OR for abdominal distension 0.4 95%CI 0.1-0.98) at diagnosis were associated with NRCD. NRCD was attributed to a wide variety of diagnoses with gluten exposure (30%) and constipation (20%) being the most common causes. Other causes for NRCD included lactose intolerance (9%), gastroesophageal reflux (8%), functional abdominal pain (7%), irritable bowel syndrome (3%), depression/anxiety (3%), eosinophilic esophagitis (2%), food allergy (1%), eating disorder (1%), gastric ulcer with Helicobacter pylori (1%), lymphocytic colitis (1%), aerophagia (1%) and undetermined (13%). 64% of children with NRCD improved on follow-up.CONCLUSIONNRCD after ≥ 6 mo GFD is frequent among children, especially females, and is associated with initial presenting symptoms of constipation and/or abdominal pain. Gluten exposure is the most frequent cause.